EP0014966B1 - Des-a-steroids, their production and some des-a-steroids for use as medicines - Google Patents

Description

The present invention relates to new deA steroids, a process for their preparation and deA steroids for use as pharmaceuticals.

worin R¹ und R² Wasserstoff oder C_1-5-Alkyl ; R³ Wasserstoff, Methyl oder Halogen ; R⁴ Wasserstoff oder, falls R³ Methyl ist, Wasserstoff oder Methyl ; R⁵ Wasserstoff, Cyano, C_1-5-Alkoxy, oder einen Rest SR⁷; oder R³ und R⁵ zusammen Methylen ; R⁶ Wasserstoff oder C_1-7-Alkanoylthlo ; R⁷ C_1-7-Alkanoyl, C_1-8-Alkyl, Benzyl oder Phenäthyl ; X Oxo oder Methylen ; Y Wasserstoff ; Z Hydroxymethyl oder eine Gruppe -COA; A Hydroxy ; oder Y und A zusammen O―C-Bindung bedeuten ; n 0 oder 1 ist und die punktierten ringständigen Bindungen fakultativ sind : wobei jeder Ring höchstens eine Doppelbindung enthalten soll ; der Ring B 9(10)-ungesättigt ist, wenn der Ring C 11(12)-ungesättigt ist ; mindestens ein Rest R⁵ oder R⁶ Wasserstoff ist ; R⁵ Wasserstoff ist, wenn R⁴ Methyl ist ; R⁵ Wasserstoff ist oder R³ und R⁵ zusammen Methylen sind, und R⁶ Wasserstoff ist, wenn Z Carboxy ist; R³ Wasserstoff, Methyl oder Halogen ist und R⁴ abwesend ist, wenn eine 6(7)- oder 7(8)-Doppelbindung vorliegt ; die 6(7)- und 11(12)-Bindung gesättigt ist, wenn R⁶ C_1-7-Alkanoylthio ist ; und R¹ abwesend und R² C_1-5-Alkyl ist, wenn eine 9(10)-Doppelbindung vorliegt, die Ringe C und D gesättigt sind, n = 0 ist und Z eine Gruppe ―COA ist, wobei Verbindungen der Formel 1, in denen Z eine Carboxylgruppe ist, auch als Salze vorliegen können.The deA steroids for use as pharmaceuticals have the general formula

wherein R ¹ and R ^{2 are} hydrogen or C _1-5 alkyl; R ^{3 is} hydrogen, methyl or halogen; R ^{4 is} hydrogen or, if R ^{3 is} methyl, hydrogen or methyl; R ^{5 is} hydrogen, cyano, C _1-5 alkoxy, or a radical SR ⁷ ; or R ³ and R ⁵ together methylene; R ^{6 is} hydrogen or C _1-7 alkanoylthlo; R ^{7 is} C _1-7 alkanoyl, C _1-8 alkyl, benzyl or phenethyl; X oxo or methylene; Y is hydrogen; Z hydroxymethyl or a group -COA; A hydroxy; or Y and A together represent an O ― C bond; n is 0 or 1 and the dotted ring bonds are optional: each ring should contain at most one double bond; ring B 9 (10) is unsaturated when ring C 11 (12) is unsaturated; at least one R ⁵ or R ^{6 is} hydrogen; R ^{5 is} hydrogen when R ^{4 is} methyl; R ^{5 is} hydrogen or R ³ and R ⁵ together are methylene and R ^{6 is} hydrogen when Z is carboxy; R ^{3 is} hydrogen, methyl or halogen and R ^{4 is} absent when there is a 6 (7) or 7 (8) double bond; the 6 (7) and 11 (12) bond is saturated when R ^{6 is} C _1-7 alkanoylthio; and R ^{1 is} absent and R ^{2 is} C _1-5 alkyl when there is a 9 (10) double bond, the rings C and D are saturated, n = 0 and Z is a group ―COA, where compounds of formula 1 in which Z is a carboxyl group can also be present as salts.

A preferred C _1-7 alkanoyl group is acetyl. The term C _1-8 alkyl is intended to include straight-chain or branched aliphatic or cycloaliphatic hydrocarbon radicals having up to 8 carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl, butyl, cyclopentyl, cyclohexyl.

In particular, alkali metal salts, e.g. B. Na and K, and NH ₄ salts, also alkaline earth metal salts, such as Ca salts into consideration. The K salts are preferred.

worin R¹, R², R³, R⁵, A, Y, n und die punktierten Bindungen die oben angegebene Bedeutung haben.A preferred group of compounds of formula I are those of the formula

wherein R ¹ , R ² , R ³ , R ⁵ , A, Y, n and the dotted bonds have the meaning given above.

DeA steroids of formula I or 1-1, in which the rings B and C are unsaturated, are new and as such are also the subject of the invention.

Another preferred group of compounds of formula I are those in which Z is hydroxymethyl.

Compounds of the formulas I and 1-1 in which at least one radical R ¹ and R ^{2 is} C _1-5 alkyl are also preferred.

In deA steroids of the formula I, in which the carbon atoms in positions 6 and 7 do not have a double bond, substituents R ³ , R ⁴ and R ^{5 located there can have} a or β configuration, 6a and 7a substituted compounds are preferred.

in der R¹, R², R³, R⁴, R⁵, R⁶, Y, Z, n und die punktierten Bindungen die den in der Formel I angegebene Bedeutung haben und in den die Ringe B und C ungesättigt sind, können erfindungsgemäss dadurch erhalten werden, dass man

• a) in einer Verbindung der Formel
  
  die Gruppe OR⁸ zur Oxogruppe oxydiert ; oder
• b) eine Verbindung der Formel
  
  oder die entsprechende Säure oder ein Salz davon in 6(7)- oder 7(8)-Stellung dehydriert ; oder
• c) eine Verbindung der Formel
  
  oder die entsprechende Säure oder ein Salz davon halogeniert ; oder
• d) eine Verbindung der Formel
  
  oder
  
  mit einer Verbindung R⁷SH, einem C_1-5 Alkanol, oder Cyanwasserstoff umsetzt ; oder
• e) eine Verbindung der Formel
  
  oder
  
  mit einer Verbindung R⁶SH umsetzt; oder
• f) in einer Verbindung der Formel
  
  oder an die entsprechende Säure oder deren Salze eine Methylengruppe an die 6(7)-Doppelbindung anlagert ; oder
• g) eine Verbindung der Formel
  
  die entsprechende Säure oder ein Salz davon mit einer Methylen-phosphoniumverbindung nach Wittig umsetzt ; oder
• h) in einer Verbindung der Formel
  
  den Lactonring öffnet, oder
• i) in einer Verbindung der Formel I, in der Z die Gruppe COA darstellt, diese Gruppe zur Hydroxylmethylgruppe reduziert ;

wobei in den obigen Formeln R¹, R², R³, R⁴, X, n und die punktierten ringständigen Bindungen die oben angegebene Bedeutung haben und R⁸ Wasserstoff oder Alkyl darstellt.The new deA steroids of the formula

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Z, n and the dotted bonds have the meaning given in formula I and in which the rings B and C are unsaturated can be obtained according to the invention in that

• a) in a compound of the formula
  
  the group OR ⁸ oxidized to the oxo group; or
• b) a compound of the formula
  
  or dehydrates the corresponding acid or salt thereof in the 6 (7) or 7 (8) position; or
• c) a compound of the formula
  
  or halogenate the corresponding acid or salt thereof; or
• d) a compound of the formula
  
  or
  
  with a compound R ⁷ SH, a C _1-5 alkanol, or hydrogen cyanide; or
• e) a compound of the formula
  
  or
  
  reacts with a compound R ⁶ SH; or
• f) in a compound of the formula
  
  or a methylene group is attached to the 6 (7) double bond on the corresponding acid or its salts; or
• g) a compound of the formula
  
  reacting the corresponding acid or a salt thereof with a methylene phosphonium compound according to Wittig; or
• h) in a compound of the formula
  
  opens the lactone ring, or
• i) in a compound of the formula I in which Z represents the group COA, this group is reduced to the hydroxylmethyl group;

wherein in the above formulas R ¹ , R ² , R ³ , R ⁴ , X, n and the dotted ring bonds have the meaning given above and R ^{8 represents} hydrogen or alkyl.

The oxidation according to process variant a) can be carried out with CR ^VI reagents, in particular Cr0 ₃ / H ₂ S0 ₄ (Jones' reagents). The oxidation is generally carried out at temperatures up to room temperature. In the oxidation of compounds with A = alkyl, such as. B. methyl, it may be appropriate at elevated temperature, for. B. to work at 50 ° C.

The dehydrogenation according to process variant b) is preferably carried out in a manner known per se by halogenation, in particular bromination, followed by dehydrohalogenation (dehydrobromination). The bromination can be carried out using brominating agents such as bromine or pyridinium hydrobromide perbromide; dehydrohalogenation with bases such as collidine, pyridine or lithium bromide / lithium carbonate / dimethylformamide. The dehydration can also be carried out directly, e.g. B. with oxidizing agents such as dichlorodicyanobenzoquinone or chloranil.

The dehydrogenation carried out in this way yields a 6 (7) unsaturated deA steroid of the formula I. A 7 (8) unsaturated deA steroid of the formula can be obtained by deconjugation of the'6 (7) double bond, e.g. B. by converting the 6 (7) unsaturated compound into a 3-enol ether, e.g. B. by treatment with orthoformate / p-toluenesulfonic acid and careful saponification of the latter, e.g. B. with weak acids such as formic acid or acetic acid at low temperatures, e.g. B. at 0 ° C can be obtained.

The halogenation of a compound of formula Ib (process variant c) can be carried out in a manner known per se, e.g. B. by reaction with a halogenating agent, such as an N-chloramide or imide (z. B. N-chlorosuccinimide) or with elemental chlorine [cf. J. Am. Chem, 72, 4534 (1950)], or by converting a compound of formula Ib into a 3-enol ester or 3-enol ether, e.g. B. the 3-enol acetate, transferred and then with chlorine [cf. J. Am. Chem. Soc. 82, 1230 (1960)]; with an N-chloroimide [cf. J. Am. Chem. Soc. 82, 1230 (1960)]; 77, 3827 (1955) or perchloryl fluoride [cf. J. Am. Chem. Soc. 81, 5259 (1959); Chem. And Ind. 1959, 1317]. Trifluoromethyl hypofluorite can also be used as the fluorinating agent.

The introduction of a substituent R ⁵ into a compound of the formula Ic or ld (process variant d) can be carried out in a manner known per se by treatment with a compound R ^S SH, such as a mercaptan, e.g. As methyl or ethyl mercaptan or a thiocarboxylic acid, e.g. B. thioacetic acid, or with an appropriate alcohol, for. As methanol or benzyl alcohol. The reaction can be carried out in an inert solvent such as an ether, e.g. B. dioxane or tetrahydrofuran, or an alcohol such as methanol or ethanol, or in a chlorinated hydrocarbon such as chloroform; the reagent, e.g. B. the thiocarboxylic acid expediently used in excess and can serve as a solvent.

To introduce the cyano group, the hydrogen cyan is conveniently generated in situ, e.g. B. from a cyanohydrin such as acetone cyanohydrin.

The introduction of the substituent R ⁶ into a compound of the formulas le and lf (process variant e) can be carried out in analogy to process variant d) by treating the starting materials with a thiocarboxylic acid, for. B. thioacetic acid.

• Die Wittig-Reaktion gemäss Verfahrensvariante g) wird in an sich bekannter Weise in Gegenwart einer starken Base, wie z. B. Buttyllithium, Natriumhydrid, k-tert.-Butylat oder dem Natriumsalz von Dimethylsulfoxid in einem Lösungsmittel, z. B. einem Aether wie Tetrahydrofuran durchgeführt.

The methylenation according to process variant f) can be carried out in a manner known per se, e.g. B. using trimethylsulfoxonium iodide in the presence of a base such as sodium hydride or potassium t-butoxide, in an aprotic dipolar solvent such as dimethyl sulfoxide, tetrahydrofuran, hexamethylphosphoric triamide, dimethylformamide or mixtures thereof, at a temperature between about 0 and 50 ° C, conveniently at room temperature :

• The Wittig reaction according to process variant g) is carried out in a manner known per se in the presence of a strong base, such as, for. B. butyllithium, sodium hydride, k-tert-butoxide or the sodium salt of dimethyl sulfoxide in a solvent, e.g. B. an ether such as tetrahydrofuran.

The lactone ring can be split in accordance with process variant h) in a manner known per se, e.g. B. using a base such as potassium or sodium hydroxide in a solvent, e.g. B. an optionally aqueous alcohol such as (aqueous) methanol, ethanol or isopropanol, at a temperature between about 0 ° C and the reflux temperature of the reaction mixture, advantageously at about 50 ° C. The salts obtained in this way, corresponding to the base used, can be acidified, e.g. B. by means of hydrochloric acid, are converted into the free acids. The latter can be converted into salts by reaction with suitable bases.

The reduction according to process variant i) can be carried out in a known manner for the reduction of lactones to alcohols, e.g. B. with complex metal hydrides such as LiAIH ₄ .

z. B. Methylcycloketol (nd-Alkyl = Methyl, n = 0, Doppelbindung abwesend) wird mit einem nieder-Alkyljodid z. B. Methyljodid reduktiv alkyliert (J.A.C.S. 89, 54-64 (1967)). Danach wird die Oxogruppe ketalisiert, die Hydroxygruppe zum 17-Keton oxydiert und mit der Lithiumverbindung von 3-Brompropionaldehyd-dimethylacetal umgesetzt. Danach wird die Dimethylacetalgruppe und die ringständige Ketalgruppe hydrolysiert. Man erhält so eine Verbindung der Formel II, in der R¹ und R² nieder-Alkyl darstellen und in der die 9(11)-Stellung (Steroidnomenklatur) gesättigt ist. Entsprechende 9(11)-ungesättigte Verbindungen der Formel II können wie folgt hergestellt werden : Eine Verbindung der Formel III wird in den tert.Butyläther übergeführt und dieser mit einem nieder-Alkyljodid, z. B. Methyljodid in tert.Butanol in Gegenwart von Kalium-tert.-butylat behandelt, wobei Verbindungen der Formel IV und V erhalten werden.

The starting compounds of formula II can be prepared as follows: a compound of formula
- (See the figure, page 7 f.)

e.g. B. methylcycloketol (nd-alkyl = methyl, n = 0, double bond absent) with a lower alkyl iodide z. B. methyl iodide reductively alkylated (JACS 89, 54-64 (1967)). The oxo group is then ketalized, the hydroxy group is oxidized to the 17-ketone and reacted with the lithium compound of 3-bromopropionaldehyde dimethylacetal. The dimethylacetal group and the ring-like ketal group are then hydrolyzed. This gives a compound of the formula II in which R ¹ and R ^{2 are} lower alkyl and in which the 9 (11) position (steroid nomenclature) is saturated. Corresponding 9 (11) -unsaturated compounds of the formula II can be prepared as follows: A compound of the formula III is converted into the tert-butyl ether and this is mixed with a lower alkyl iodide, e.g. B. treated methyl iodide in tert-butanol in the presence of potassium tert-butoxide, whereby compounds of formula IV and V are obtained.

durch Hydrierung der konjugierten Doppelbindung, z. B. mit Pd/H₂ und gegebenenfalls nachfolgenden 6(7)-Dehydrierung, die in Analogie zu Verfahrensvariante b) ausgeführt werden kann, erhalten werden.After cleavage of the tert-butyl ether, the ring-like oxo group is ketalized and the spirolactone group is built up in the manner described above. Compounds of the formula II with R ¹ and R ² = hydrogen can be obtained from compounds of the formula

by hydrogenating the conjugated double bond, e.g. B. with Pd / H ₂ and optionally subsequent 6 (7) dehydrogenation, which can be carried out in analogy to process variant b).

Compounds of the formula II in which R3 and R ^{4 are} methyl can be prepared from compounds of the formulas IV, V or VI by methylation with methyl iodide in the presence of lithium diisopropylamide in a manner known per se.

A double bond in the 11 (12) position can be converted into corresponding 11 (12) -saturated starting materials, e.g. B. Compounds of formula II with saturated C-ring, by treatment with dehydrogenating agents such as chloranil, are introduced in a manner known per se.

Otherwise, the starting materials can be prepared as described in the examples or in analogy.

The compounds of the formula and the salts thereof can be used as pharmaceuticals. Among other things, they are diuretically active and are suitable for blocking the action of aldosterone or deoxycorticosterone acetate and can therefore be used, for example, as potassium-sparing diuretics or for washing out edema.

From US-A-2971 009 and J. Org. Chem. 26 (1961), 3910-3915, deA steroids with a 17-spirolactone group are known which have an inhibitory effect on the Na-retentive activity of mineralocorticoids. From US-A-3 412 107 deA steroids with a 17-spirolactone grouping are known, which are intermediates in steroid synthesis.

• A 5-Oxo-A-tetranor-10α,17a-pregn-6-en-21,17-carbolacton
• B :7a-(Acetylthio)-5-oxo-A-tetranor-10a,17a-pregnan-21,17-carbolacton
• C Kalium-17-hydroxy-5-oxo-A-tetranor-10α,17a-pregn-6-en-21-carboxylat
• D :5-Oxo-1,5-seco-A-trinor-17α-pregnan-21,17-carbolacton
• E :7α-(Acetytthio)-5-oxo-1,5-seco-A-trinor-17α-pregnan-21,17-carbolacton
• F : Kalium-17-hydroxy-5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21-carboxylat
• G 6-Brom-5-oxol-1,5-seco-A-trinor-17α-pregn-6-en-21,17-carbolacton
• H . .5-Oxo-A-tetranor-17a-pregna-9,11-dien-21,17-carbolacton
• I : 7α-(Aethylthio)-5-oxo-1,5-seco-A-trinor 17α-pregnan-21,17-carbolacton
• J : 7α-Cyano-5-oxo-1,5-seco-A-trinor-17a-pregnan-21,17-carbolacton
• K : Kalium-17-hydroxy-5-oxo-1,5-seco-A-trinor-17a-pregna-6,9(11)-dien-21-carboxylat
• I 6α-Methyl-5-oxo-1,5-seco-A-trinor-17a-pregn-9(11)en-21,17-carbolacton
• M : 7α-(Acetylthio)-5-oxo-3,5-seco-A-nor-10α,17a-pregnan-21,17-carbolacton
• N 6,6-Dimethyl-5-oxo-1,5-seco-A-trinor-17a-pregn-9(11)-en-21.17-carbolacton

The aldosterone antagonistic effect was determined using the experimental set-up described below: Female Holtzman rats (150-180 g) were bilaterally adrenalectomized 70-74 hours before the experiment. After the operation, the animals received 0.9% NaCI solution as drinking water and commercially available dry food. The feed was discontinued 16-17 hours before the experiment while the saline solution remained available ad libitum. Sodium and potassium in the urine were determined by flame photometry. The test substances were dissolved in 0.3% NaCl solution and administered in an amount of 30 ml / kg by gastric tube. In each experiment, a control group was carried out, which was treated identically, but instead of the test substances received the same volume of pure NaCl solution. 30 minutes later, Aldosteren was injected subcutaneously. 120 minutes after the administration of the test substances, the urinary bladders of the animals were emptied by slight suprapubic pressure. The animals were then placed in metabolic cages without access to food and water. The urine was collected every 3 hours and the blisters were finally expressed. The spontaneous urine and the residual urine were collected. The results are shown in the table below (urine volume V, Na ⁺ and K ⁺ in% of the control group).

• A 5-Oxo-A-tetranor-10α, 17a-pregn-6-en-21,17-carbolactone
• B: 7a- (acetylthio) -5-oxo-A-tetranor-10a, 17a-pregnan-21,17-carbolactone
• C Potassium 17-hydroxy-5-oxo-A-tetranor-10α, 17a-pregn-6-en-21-carboxylate
• D: 5-Oxo-1,5-seco-A-trinor-17α-pregnan-21,17-carbolactone
• E: 7α- (Acetytthio) -5-oxo-1,5-seco-A-trinor-17α-pregnan-21,17-carbolactone
• F: Potassium 17-hydroxy-5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21-carboxylate
• G 6-bromo-5-oxol-1,5-seco-A-trinor-17α-pregn-6-en-21,17-carbolactone
• H . .5-Oxo-A-tetranor-17a-pregna-9,11-diene-21,17-carbolactone
• I: 7α- (ethylthio) -5-oxo-1,5-seco-A-trinor 17α-pregnan-21,17-carbolactone
• J: 7α-Cyano-5-oxo-1,5-seco-A-trinor-17a-pregnan-21,17-carbolactone
• K: Potassium 17-hydroxy-5-oxo-1,5-seco-A-trinor-17a-pregna-6,9 (11) -diene-21-carboxylate
• I 6α-methyl-5-oxo-1,5-seco-A-trinor-17a-pregn-9 (11) en-21,17-carbolactone
• M: 7α- (acetylthio) -5-oxo-3,5-seco-A-nor-10α, 17a-pregnan-21,17-carbolactone
• N 6,6-dimethyl-5-oxo-1,5-seco-A-trinor-17a-pregn-9 (11) -en-21.17-carbolactone

The compounds of formula I and their salts can be used as medicaments, for. B. in the form of pharmaceutical preparations are used, which they or their salts in a mixture with a suitable for enteral or parenteral application organic or inorganic inert carrier material, such as. As water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. contain. The pharmaceutical preparations can be in solid form, e.g. B. as tablets, dragees, suppositories, capsules; or in liquid form, e.g. B. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.

The pharmaceuticals can be prepared in a manner known per se by combining the compound of the formula I or a salt thereof with non-toxic, inert solid and / or liquid carrier materials which are conventional in such preparations, such as, for example, for therapeutic administration. B. the above, mixed and optionally brings into the desired shape. The dose unit for administration to adults is approximately 0.1-10 mg / kg per day.

example 1

To a solution of 9.6 g of 5-oxo-1,5-seco-A-trinor-17α-pregna-21,17-carbolactone in 100 ml of tetrahydrofuran, a solution of 22.9 g of 2-carboxy- Ethyl triphenylphosphonium perbromide added dropwise in 125 ml of tetrahydrofuran. After stirring for 2 hours at room temperature, the reaction mixture is poured onto ice water and extracted with methylene chloride. The crude product obtained by working up the methylene chloride extract is boiled for 1 hour under argon with a mixture of 105 ml of dimethylformamide, 10.5 g of lithium bromide and 10.5 g of lithium carbonate. The cooled solution is poured onto water and extracted with a mixture of ether-methylene chloride (4: 1). Chromatography of the residue obtained from the extract on silica gel with toluene-ethyl acetate (7: 3) gives 5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21,17-carbolactone as the main product , Melting point 128-129 ° (from diethyl ether); [α] D ^{25 to} 112.5 ° (dioxane, c = 0.2).

A by-product is 6-bromo-5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21,17-carboiactone, melting point 194-195 ° (from diethyl ether-methylene chloride); [α] _D ²⁵ - 38 ° (dioxane, c = 0.2)

Example 2

Analogously to Example 1, 5-oxo-1,5-seco is obtained from 5-oxo-1,5-seco-A-trinor-17a-pregn-9 (11) -en-21,17-carbolactone -A-trinor-17a-pregna-6.9 (11) -diene-21.17-carbolactone, melting point 195-197 °; [α] D ^25-292 ° (dioxane, c = 0.5).

5-Oxo-1,5-seco-A-trinor-17a-pregna-7,9 (11) -diene-21,17-carbolactone, melting point 159-160 °; Isolate [α] _D ²⁵ + 40.5 (dioxane, c = 0.2).

Example 3

Analogously to Example 1, 5-oxo-3,5-seco-A-nor-17α-pregna-21,17-carbolactone is used to obtain 5-oxo-3,5-seco-A-nor-17α-pregn- 6-en-21,17-carbolactone, melting point 181-183 °; [α] D ²⁵ - 92.5 ° (dioxane, c = 1.0).

A by-product is 6-bromo-5-oxo-3,5-seco-A-nor-17α-pregn-6-en-21,17-carbolactone, melting point 194-196 °; [α] _D ^{25 -} 40.1 ° (dioxane, c = 1.0).

Example 4

Analogously to Example 1, 5-oxo-2,5-seco-A-dinor-17a-pregnan-21,17-carbolactone is used to obtain 5-oxo-2,5-seco-A-dinor-17a-pregnane 6-en-21,17-carbolactone, melting point 157-159 °; [a] ²⁵ -101; 3 ° (dioxane, c = 1.0).

The by-product obtained is 6-bromo-5-oxo-2,5-seco-A-dinor-17a-pregn-6-en-21,17-carbolactone, melting point 194-196 °; [α] _D ²⁵ - 48 ° (dioxane, c = 1.0).

Example 5

Analogously to Example 1, 6-methyl-5-oxo-1; 5 is obtained from 6-methyl-5-oxo-1,5-seco-A-trinor-17a-pregnan-21,17-carbolactone -seco-A-trinor-17α-pregn-6-en-21,17-carbolactone, melting point 181-182 °; [a] D25 - 86 ° (dioxane, c = 0.5).

Example 6

Analogously to Example 1, 6-methyl-5-oxo is obtained from 6-methyl-5-oxo-1,5-seco-A-trinor-17a-pregn-9 (11) -en-21,17-carbolactone -1,5-seco-A-trinor-17a-pregna-6,9 (11) -diene-21,7-carbolactone, melting point 195-198 °; [α] _D ²⁵ - 256.4 ° (dioxane, c = 0.5).

Example 7

Analogously to example 1, 5-oxo-3,5-seco-A-nor-10α, 5a-3,5-seco-A-nor-10α, is obtained from 5-oxo-3,5-seco-A-nor-10α, 17α-pregn-6-en-21,17-carbolactone, melting point 149-1500; [α] _D ^{25 to} 119.2 ⁰ (dioxane, c = 0.5).

A by-product is 6-bromo-5-oxo-3,5-seco-A-nor-10a, 17a-pregn-6-en-21,17-carbolactone, melting point 179-180 °.

• Methylcycloacetal wird mit n-Propyljodid reduktiv alkyliert. Man erhält 17ß-Hydroxy-3,5-seco-A-nor-10a-androstan-5-on, Schmelzpunkt 117-118,5° und daraus durch Ketalisierung das 17ß-Hydroxy-3,5- seco-A-nor-10a-androstan-5-on-äthylen-acetal, Schmelzpunkt 153-154°.

The starting material is produced as follows:

• Methylcycloacetal is reductively alkylated with n-propyl iodide. 17β-Hydroxy-3,5-seco-A-nor-10a-androstan-5-one is obtained, melting point 117-118.5 ° and the 17β-hydroxy-3,5-seco-A-nor- 10a-androstan-5-one-ethylene-acetal, melting point 153-154 °.

Oxidation with pyridinium chlorochromate yields 3,5-seco-A-nor-10a-androstane-5,17-dione-5- (ethyleneacetal), [α] _D - 108 ° (dioxane 0.36) from which in analogy to Example 41 5-Oxo-3,5-seco-A-nor-10α, 17α-pregnan-21,17-carbolactone, melting point 150-151 ° is obtained.

Example 8

6 g of 5-oxo-A-tetranor-10α-17α-pregnan-21,17-carbolactone are dissolved in 900 ml of ether and cooled to about 3 ° in an ice bath. A solution of 3,368 mg of bromine in 12.42 ml of acetic acid is added dropwise to the solution with stirring over the course of 10 minutes. Sodium sulfite solution is added to the practically colorless solution and then extracted with diethyl ether. Evaporation of the extract gives 8.62 g of colorless oil, which is boiled under argon for 1 hour with a suspension of 6 g of lithium carbonate and 6 g of lithium bromide. After working up the reaction mixture and chromatography of the residue on silica gel with toluene-ethyl acetate (9: 1), 5-oxo-A-tetranor-10α, 17α-pregn-6-en-21,17-carbolactone are obtained.

Example 9

To a solution of 10 g of 5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21,17-carbolactone in 330 ml of pyridine, cooled to 15 °, 5,6 ml of sulfuryl chloride added. The reaction solution is kept at 15 ° for 1 hour, then poured onto ice water and extracted with ether. The ethereal extract is washed with dilute hydrochloric acid and water, dried over sodium sulfate and under evaporated under reduced pressure. The residue is chromatographed on 800 g of silica gel. With toluene-ethyl acetate (95: 5), 1.8 g of pure 6-chloro-5-oxo-1,5-seco-A-trinor-17a-pregn-6-ene-21,17-carbolactone, melting point 220-223 ° (from acetone-hexane); [α] _D ^{25 to} 57.2 ° (dioxane, c = 1.0) is eluted.

Example 10

658 mg of 6-bromo-5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21,7-carbolactone are suspended in a mixture of 10 ml of methanol and 2.15 ml of water. 2.15 ml of thioacetic acid are added to this suspension under argon. After 3 hours the reaction mixture is diluted with water. The residue is filtered off, dried and crystallized twice from acetone. This gives 7a- (acetylthio) -6a-bromo-5-oxo-1,5-seco-A-trinor-17a-pregnan-21,17-carboiactone, melting point 178-181 ° (decomposition); [α] _D ^{25 to} 18.4 ° (dioxane, c = 0.5).

Example 11

520 mg of 6-bromo-5-oxo-1,5-seco-A-trinor-17α-pregn-6-en-21,17-carbolactone are dissolved in 15 ml of isopropanol. The solution is mixed with 0.68 ml of 2N potassium hydroxide solution and the reaction mixture is left to stand under an argon atmosphere for 2 hours. After evaporating the reaction mixture, a strongly hygroscopic foam of potassium 6-bromo-17-hydroxy-5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21-carboxylate, [α] _D ^{25 to} 55.5 ° (ethanol, c = 0.2).

Example 12

In analogy to Example 11, 6-chloro-17-hydroxy-5 is obtained from 6-chloro-5-oxo-1,5-seco-A-trinor-17α-pregn-6-en-21,17-carbolactone -oxo-1,5-seco-A-trinor-17α-pregn-6-en-21-carboxylate as an amorphous substance, [α] _D ^{25 -} 67.1 ° (methanol, c = 1.0).

Example 13

4.4 g of trimethylsulfoxonium iodide and 0.82 g of sodium hydride dispersion (50% in mineral oil) are mixed with 15 ml of dimethyl sulfoxide under an argon atmosphere at about 15 °. After stirring for 2 hours at room temperature, the mixture is mixed with a solution of 3.02 g of 5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21,17-carbolactone in 15 ml of dimethyl sulfoxide. The reaction mixture is stirred under argon overnight at room temperature and then 1 ml of glacial acetic acid is added dropwise at 10 °. The reaction mixture is then poured into water, extracted with ether, the extract washed, dried and evaporated. The residue is chromatographed on silica gel with hexane-ether (2: 1) and, after crystallization from methylene chloride-diethyl ether-hexane, gives pure 6,7-dihydro-5-oxo-3'H-cyclopropa [6.7] -1.5 -seco-A-trinor-17 _α -pregn-6-en-21,17-carbolactone in two diastereomeric forms. One isomer (presumably the 6ß, 7ß-dihydro form) shows a melting point 214-216 °; [α] _D ^25-105 ° (dioxane, c = 0.5). The other isomer (presumably the 6a, 7a-Dihydro-form) melts at 178-179 °, [α] _D ^25-113 ° (dioxane, c = 0.2).

Example 14

5.64 ml of 2N potassium hydroxide solution are added to a solution of 3.5 g of 5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21,17-carbolactone in 123 ml of isopropanol. The reaction mixture. is stirred for 2 hours under argon at room temperature. For working up, part of the isopropanol (about 70%) is distilled off, and after cooling the potassium 17-hydroxy-5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21-carboxylate crystallized in the form of colorless hygroscopic crystals. Melting point 240-242 ° (decomposition); [α] _D ^{25 to} 120.5 ° (ethanol, c = 0.2).

Example 15

In analogy to example 14, the potassium 17-hydroxy-5-oxo is obtained from 5-oxo-1,5-seco-A-trinor-17a-pregna-6,9 (11) -diene-21,17-carbolactone -1,5-seco-A-trinor-17α-pregna-6,9 (11) -diene-21-carboxylate, melting point from 110 ° (beginning of decomposition); [α] _D ^25-242 ° (ethanol, c = 0.2).

Example 16

Analogously to Example 14, the potassium 17-hydroxy-6-methyl- is obtained from 6-methyl-5-oxo-1,5-seco-A-trinor-17α-pregn-6-en-21,17-carbolactone. 5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21-carboxylate as a strongly hygroscopic foam, melting point 265-268 ° (decomposition); [α] _D ^{25-96 0} (ethanol, c = 0.5).

Example 17

Analogously to Example 14, 6-methyl-5-oxo-1,5-seco-A-trinor-17a-pregna-6.9 (11) dien) 21,17-carbolactone, the potassium 17-hydroxy-6-methyl-5-oxo-1; 5-seco-A-trinor-17α-pregna-6,9 (11) -the-21-carboxylate , Melting point 160-165 °; [α] _D ^{25 to} 230.5 ° (ethanol, c = 0.2).

Example 18

In analogy to Example 14, the potassium 17-hydroxy-5-oxo-3 is obtained from 5-oxo-3,5-seco-A-nor-10-17-pregn-6-en-21,17-carbolactone, 5-seco-A-nor-10α, 17α-pregn-6-en-21-carboxylate, melting point 256-260 °; [α] D ²⁵ - 121.4 ° (ethanol, c = 0.5).

Example 19

In analogy to Example 14, the potassium 17-hydroxy-5-oxo-A-tetranor-10α is obtained from 5-oxo-A-tetranor-10a, 17a-pregn-6-en-21,17-carbo) acton, 17α-pregn-6-en-21-carboxylate, melting point 225-230 ° (decomposition); [α] _D ^25-102 ° (dioxane, c = 0.2).

Example 20

Analogously to Example 14, 6,7-dihydro-5-oxo-3'H-cyclopropa [6,7] -1,5-seco-A-trinor-17a-pregn-6-en-21.17 is obtained -carbolactone the potassium-6,7-dihydro-17-hydroxy-5-oxo-3'H-cyclopropa [6,7] -1,5-seco-A-trinor-17a-pregn-6-en-21- carboxylate, melting point 265-267 °; [a] D ^25-86 ° (dioxane, c = 0.5).

Example 21

Analogously to Example 14, the potassium 17-hydroxy-5-oxo-3,5- is obtained from 5-oxo-3,5-seco-A-nor-17α-pregn-6-en-21,17-carbolactone. seco-A-nor-17a-pregn-6-en-21-carboxylate as an amorphous substance, [α] _D ²⁵ - 86.4 ° (methanol, c = 1).

Example 22

5 g of 5-oxo-1,5-seco-A-trinor-17α-pregn-6-en-21,17-carbolactone are suspended in 20.5 ml of methanol and 4.4 ml of water. 4.4 ml of thioacetic acid are added dropwise to the suspension over 10 minutes under argon. After stirring for 3 hours at room temperature, no starting material can be detected on the thin layer chromatogram. The solution is then poured onto ice water, the precipitate is filtered off and recrystallized from methanol-water. This gives 7a- (acetylthio) -5-oxo-1,5-seco-A-trinor-17a-pregnan-2,17-carbolactone with a melting point of 147-148 °; [α] _D ²⁵ - 27 ° (dioxane, c = 0.2).

Example 23

In analogy to Example 22, 5α-1,5-seco-A-trinor-17α-pregna-6,9 (11) -diene-21,17-carbolactone n is 7α- (acetylthio) -5- oxo-1,5-seco-A-trinor-17α-pregn-9 (11) -en-21,17-carbolactone. melting point 153-154 °; [α] _D ²⁵ -113 ° (dioxane, c = 0.2), and the 7β- (acetylthio) -5-oxo-1,5-seco-A-trinor-17a-pregn-9 (11) -en -21,17-carbolactone, melting point 158-162 °; [α] _D ^{25 to} 84.5 ° (dioxane, c = 0.2).

Example 24

Analogously to Example 22, 6-methyl-5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21,17-carbolactone is obtained after chromatography of the reaction product on silica gel with hexane-ethyl acetate ( 4: 1) the 7α- (acetylthio) -6α-methyl-5-oxo-1,5-seco-A-trinor-17α-pregnan-21,17-carbolactone, melting point 203-205 °; [α] _D ²⁵ 0 ° (dioxane, c = 0.2).

Example 25

Analogously to Example 22, 7α- (acetylthio) is obtained from 6-methyl-5-oxo-1,5-seco-A-trinor-17a-pregna-6,9 (11) -diene-21,17-carbolactone -6α-methyl-5-oxo-1,5-seco-A-trinor-17α-pregn-9 (11) -en-21,17-carbolactone of melting point 207-210 °; [α] _D ^{25 -} 7.5 ° (dioxane, c = 0.2).

Example 26

In analogy to Example 22, the 7a- (acetylthio) -5-oxo- is obtained from 5-oxo-3,5-seco-A-nor-10a-17a-pregn-6-en-21,17-carbolactone. 3,5-seco-A-nor-10a, 17a-pregnan-21,17-carbolactone, melting point 168-169 °; [α] _D ^{25-18 0} (dioxane, c = 0.5).

The 7ß-isomer can be isolated from the mother liquors.

Analogously to Example 22, the 7a- (acetylthio) -5-oxo-A-tetranor-10a, 17a- is obtained from 5-oxo-A-tetranor-10α-17α-pregn-6-en-21,17-carbolactone. pregnan-21,17-carbolactone.

Example 28

Analogously to Example 22, 5α-3,5-seco-A-nor-17a-pregn-6-en-21,17-carbolactone gives 7α- (acetyithio) -5-oxo-3,5- seco-A-nor-17ot-pregnan-21,17-carboiactone, melting point 162-165 °, [a] _D ^{25 -} 17.2 ⁰ (dioxane, c = 1).

Example 29

Analogously to Example 22, the 7a- (acetylthio) -5-oxo-2,5- is obtained from 5-oxo-2,5-seco-A-dinor-17a-pregn-6-en-21,17-carbolactone. seco-A-dinor-17α-pregnan-21,17-carbolactone, melting point 194-196 °; [α] _D ²⁵ - 9 ° (dioxane, c = 1).

Example 30

Analogously to Example 22, 7α- (acetylthio) -6α-chloro is obtained from 6-chloro-5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21,17-carbolactone. 5-oxo-1,5-seco-A-trinor-17α-pregnane-21,17-carbolactone, melting point 204-209 °: [α] _D ^{25 to} 17.3 °.

Example 31

In analogy to Example 22, 7a- (propionylthio) -5-oxo-1 is obtained from 5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21,17-carbolactone with thiopropionic acid, 5-seco-A-trinor-17a-pregnan-21,17-carbolactone, melting point 148-149 °; [α] _D ²⁵ - 31.1 °.

Example 32

A solution of 3.02 g of 5-oxo-1,5-seco-A-trinor-17ot-pregn-6-en-21,17-carbolactone in 20 ml of ethyl mercaptan and 2 ml of piperidine is kept at room temperature for 90 minutes. For working up, the solvent is evaporated under reduced pressure and the residue is recrystallized from acetone-hexane. 2.9 g of pure 7a- (ethylthio) -5-oxo-1,5-seco-A-trinor-17a-pregnan-21,17-carbolactone, melting point 180-1810; [a] _D ²⁵ - 51.9 °.

Example 33

To a solution of 2 g of 5-oxo-1,5-seco-A-trinor-17α-pregn-6-en-21,17-carbolactone in 40 ml of methanol and 4 ml of tetrahydrofuran, 2 ml of saturated sodium carbonate solution and 1.3 ml of acetone cyanohydrin added: the reaction mixture is heated to reflux with stirring for 2 hours. For working up, the solution is cooled, poured onto ice water and extracted with ether. The ethereal extracts provide 2.2 g of colorless crystals which, after chromatography on silica gel and crystallization from acetone-hexane, give pure 7a-cyano-5-oxo-1,5-seco-A-trinor-17a-pregnan-21,17-carbo- give lactone. Melting point 240-241 ⁰ ; [a] _D ^{25 -} 5.7 °.

Example 34

In analogy to example 1, 5-oxo-1,5-seco-A-trinor-17a-pregna-21,17-carbolactone is reacted with 2.2 mol equivalents of bromine. After working up as in Example 1, the 6-bromo-5-oxo-1,5-seco-A-trinor-17α-pregn-6-en-21,17-carbolactone is obtained as the main product.

Example 35

1,500 mg of 5-oxo-1,5-seco-A-trinor-17α-pregn-6-en-21,17-carbolactone in a mixture of 30 ml of methanol and 4 ml of aqueous 2N sodium hydroxide solution for 7 days under argon Reflux heated. The reaction mixture is then diluted with water, acidified with 2N hydrochloric acid and extracted with ether-methylene chloride (4: 1). The organic phases are washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on 100 times the amount of silica gel using toluene-ethyl acetate (19: 1). As a non-polar product, 5-oxo-1,5-seco-A-trinor-17α-pregn-7-en-21,17-carboiactone is first isolated, which melts at 153-157 ° after crystallization from acetone-hexane. [α] _D = 8.5 ° (dioxane, c = 0.2). From the subsequent fractions, unreacted starting material, 7a-methoxy-5-oxo-1,5-seco-A-trinor-17a-pregnan-21,17- carbolactone, melting point 138-142 ° (from ether), [α] _D - 12.5 ° (dioxane, c = 0.2) and 7-methoxy-5-oxo-1,5-seco-A-trinor- 17α-pregn-6-en-21,17-carbolactone, melting point 167-169 ° (from methylene chloride ether), [α] _D - 63 ° (dioxane, c = 0.2) obtained.

Example 36

2 g of 5-oxo-A-tetranor-17 "-pregna-9,11-diene-21,17-carbolactone are dissolved in 40 ml of isopropanol and mixed with 3.42 ml of potassium hydroxide solution 2N and stirred for 1 hour in an argon atmosphere. The solution is then concentrated with repeated addition of isopropanol (azeotropic removal of the water) and 6 times the amount of acetone is added with vigorous stirring, whereupon the K salt precipitates. After cooling to + 5 ° overnight, the product is filtered off with suction and dried immediately at 80 ° in a high vacuum. This gives 1.83 g of potassium 17-hydroxy-5-oxo-A-tetranor-17a-pregna-9.11-diene-21-carboxylate, which sinters at 169 ° (then foam formation). [a] - 113.4 (EtOH 0.5), UV λ = 292 nm, s = 24 950.

The sodium 17-hydroxy-5-oxo-A-tetranor-17a-pregna-9,11-diene-21-carboxylate is prepared analogously. [α] _D - 118 ° (EtOH 0.5%), UV λ = 293 mm, ε = 22 600.

Example 37

2.6 g of 5-oxo-A-tetranor-17a-pregn-9-en-21,17-carbolactone are dissolved in 39 ml of t-butanol and refluxed together with 2.6 g of chloranil for 5 hours in an argon atmosphere . The cooled reaction product is poured onto ice water and extracted with ether. The organic phases are washed twice with 0.1N NaOH, then with brine until neutral. The crude product obtained in this way is chromatographed on 100 times the amount of silica gel using hexane-ethyl acetate 2: 1. The crude product is crystallized from acetone-isopropyl ether. This gives 5-oxo-A-tetranor-17a-pregna-9.11-diene-21.17-carbolactone, melting point 122-123 °. [a] _o ^25-211 ° (dioxane 0.2), UV λ = 289 nm, ε = 26 200th

Analogously, 5-oxo-1,2,3,4,19-pentanor-17a-pregn-9-en-21,17-carbolactone gives 5-oxo-1,2,3,4,19-pentanor- 17a-pregna-9,11-diene-21,17-carbolactone. Melting point 153-154 ° (from methylene chloride / ether), UV λMAX = 180 nm, ε = 27,000 _. [α] _D - 234 ° (dioxane 0.5%).

Example 38

433 mg of 5-oxo-A-fetranor-17α-pregna-9.11-diene-21.17-carbolactone are dissolved in 8.7 ml of isopropanol and 8.7 ml of water. 56.4 mg of calcium hydroxide are added to the solution. The mixture is stirred in an argon atmosphere at 50 ° for 2 hours and then the reaction solution is concentrated with repeated addition of isopropanol. After adding ethyl acetate, the product is filtered off and dried. This gives 386 mg of calcium 17-hydroxy-5-oxo-A-tetranor-17α-pregna-9,11-diene-21-carboxylate.

. Example 39

300 mg of lithium aluminum hydride are suspended in 37.9 ml of tetrahydrofuran. A solution of 1.6 5-oxo-A-tetranor-17α-pregna-9.11-diene-21.17-carbolactone in 46 ml of tetrahydrofuran is added dropwise and the mixture is then refluxed under argon for 1 hour. 2.5 ml of ethyl acetate and then 50 ml of 0.5N hydrochloric acid are added with cooling. After working up the reaction mixture, 1.5 g of crude 5.17 β-dihydroxy-17- (3-hydroxypropyl) -A-tetranorandrosta-9,11-diene are obtained.

1.1 g of the crude product thus obtained are suspended together with 1.38 g of dichlorodicyanchinone in 45.8 ml of dioxane and stirred under argon for 48 hours at room temperature. For working up, it is poured onto ice / water and extracted with ether. The extracts are washed neutral with sodium bicarbonate solution and then with saline. The crude product thus obtained is chromatographed on silica gel with hexane-toluene 1: 1 and finally with toluene. Crystallization from methylene chloride / hexane provides 400 mg of 17β-hydroxy-17- (3-hydroxypropyl) -A-tetranorandrosta-9,11-dien-5- one as yellowish crystals with a melting point of 168-169 °. [α] _D - 170 ° (dioxane 0.2%). UV λ = 292 nm, ε = 26,000.

Example 40

610 mg of 5-oxo-A-tetranor-17a-pregna-9,11-diene-21,17-carbolactone are refluxed in 5 ml of thioacetic acid for 5 hours under argon. For working up, it is poured onto ice / water and extracted with ether. The organic phases are washed first with 1N potassium hydroxide solution, then with water until neutral. After drying with magnesium sulfate and evaporation, the crude product was chromatographed on 150 g of silica gel using toluene / ethyl acetate. The fraction eluted first consists of unreacted starting material. The second fraction is crystallized twice from acetone. Isopropyl alcohol 36 mg of pure 12ß- (acetylthio) -5-oxo-A-tetranor-17a-pregn-9-ene-21,17-carbolactone melting point 195-198 ° obtained. [α] _D - 45 ° (dioxane).

Example 41

10 g of 1,5-seco-A-trinorandrostan-5,17-diene-5,5- (ethylene) acetal are dissolved in 168 ml of tetrahydrofuran and cooled to - 20 °. Now 2.35 g of finely chopped wire are added and then 36.5 g of 3-bromopropionaldehyde dimethylacetal are added dropwise within 2 hours. The cooling bath is then removed and stirring is continued for a further 1 hour, the temperature rising to room temperature. The unused lithium is filtered off and the solution is poured onto ice / water and extracted with ether, which is washed with brine. The combined extracts are dried with magnesium sulfate and concentrated on a rotary evaporator. This gives 20 g of a reddish oil, which is processed without further purification.

The oily product is dissolved in 143 ml of glacial acetic acid, 47 ml of water and 5 g of p-toluenesulfonic acid are added and the mixture is stirred overnight. For working up, it is again poured onto ice water, extracted with ether, washed neutral with sodium carbonate solution and finally with water. After drying and evaporation, 12 g of a red-brown oil are obtained, which is further processed without further purification.

The entire crude product obtained is dissolved in 61 ml of acetone and 37 ml of dichloromethane and oxidized with an excess of Jones reagent. The reaction mixture is poured onto ice water and extracted with ether, which is washed neutral with water. After drying with magnesium sulfate and concentration, 10.9 g of a yellow oil are obtained, which is chromatographed on a 100-fold amount of silica gel with toluene-ethyl acetate. Crystallization of the corresponding fractions from methylene chloride ether gives pure 5-oxo-1,5-seco-A-trinor-17α-pregnan-21,17-carbolactone. Melting point 134-135 °, [a] _D + 7 ° (dioxane 0.2) ..

• 17ß-t-Butoxy-1,5-seco-A-trinorandrost-9-en-5-on wird durch reduktive Methylierung in 17ß-t-Butoxy-1,5-seco-A-trinorandrostan-5-on, Schmelzpunkt 128-129° (aus Aether/Hexan) übergeführt.

The starting material is produced as follows:

• 17ß-t-Butoxy-1,5-seco-A-trinorandrost-9-en-5-one is obtained by reductive methylation in 17ß-t-butoxy-1,5-seco-A-trinorandrostan-5-one, melting point 128 -129 ° (from ether / hexane) transferred.

The t-butyl ether is split with acetic acid / perchloric acid. Subsequent saponification with potassium carbonate in methanol gives 17β-hydroxy-1,5-seco-A-trinorandrostan-5-one, melting point 99-100 ° (from ether / hexane).

Ketalization gives 17β-hydroxy-1,5-seco-A-trinor-androstan-5-one-ethylene acetal, melting point 168-169 ° (ether / hexane).

After oxidation with pyridinium chlorochromate, 1,5-seco-A-trinorandrostane-5,17-dione-5- (ethylene acetal) is obtained, melting point 140-141 ° (from methylene chloride / hexane). _.

Example 42

In analogy to Example 39, the 17β-hydroxy-17- (3-hydroxypropyl) -1 is obtained from 5-oxo-1,5-seco-A-trinor-17a-pregn-6-en-21,17-carbolactone, 5-seco-A-trinorandrost-6-en-5-one. Melting point 169-171 ° (crystals of acetone) UV A = 231 nm, e = 8 170, [a] p ^{25 -} 90 ° (dioxane 1.0%)

Example 43

2.5 g of 5-oxo-1,5-seco-A-trinor-17α-pregn-6-en-21,17-carbolactone and 14.77 g of triphenylmethylphosphonium bromide are dissolved in 50 ml of dimethyl sulfoxide and at room temperature under argon within 10 Minutes with a solution of 4.64 g of potassium tert-butoxylate in 50 ml of dimethyl sulfoxide. After 15 minutes the mixture was brought to pH 2 to 3 with cooling with 6N hydrochloric acid and stirred for 30 minutes. Then it was poured onto ice and extracted with ether, which was washed neutral with brine. After drying with magnesium sulfate and evaporation, 11 g of yellow oil were obtained, which were chromatographed on 500 g of silica gel with toluene / ethyl acetate 19: 1. This gives 650 mg of 1,2-seco-A-dinor-17a-pregna-2,6-diene-21,17-carboiactone, which crystallizes from methanol. Melting point 175-176 °, UV λmex 232 nm, e = 22,000, [a] _o - 64 ° (dioxane 0.2).

Example 44

5-Oxo-1,5-seco-A-trinor-17α-pregn-9 (11) -en-21,17-carbolactone, 150-151.5 ° (from methylene chloride / ether), [a] _D - 40 ° (dioxane 0.5%), is obtained from 1,5-seco-A-trinorandrost-9 (11) -en-5,17-dione-cyclic-5- (ethylene acetal) analogously to Example 41.

• 17ß-t-Butoxy-1,5-seco-A-trinorandrost-9-en-5-on wird in t-Butanol mit Kalium-t-butylat und Methyljodid methyliert. Dabei kann je nach den angewandten Bedingungen 17ß-t-Butoxy-1,5-seco-A-trinorandrost-9(11)-en-5-on, Schmelzpunkt 118° (aus Methylenchlorid/Aether) oder 17ß-t-Butoxy-6a-methyi-1,5- seco-A-trinorandrost-9(11)-en-5-on, Schmelzpunkt 147-148° (aus Methylenchlorid/Aether) als Hauptprodukt erhalten werden.

The starting material was produced as follows:

• 17ß-t-Butoxy-1,5-seco-A-trinorandrost-9-en-5-one is methylated in t-butanol with potassium t-butoxide and methyl iodide. Depending on the conditions used, 17ß-t-butoxy-1,5-seco-A-trinorandrost-9 (11) -en-5-one, melting point 118 ° (from methylene chloride / ether) or 17ß-t-butoxy- 6a-methyi-1,5-seco-A-trinorandrost-9 (11) -en-5-one, melting point 147-148 ° (from methylene chloride / ether) can be obtained as the main product.

Cleavage of the t-butyl ether with acetic acid / perchloric acid and subsequent saponification with Ka Lithium carbonate in methanol gives 17β-hydroxy-1,5 _- seco-A-trinorandrost-9 (11) -en-5-one, melting point 119-120 ° (from acetone-hexane).

Ketalization and subsequent oxidation with pyridinium chlorochromate yields 1,5-seco-A-trinorandrost-9 (11) -en-5,17-dione-5- (ethylene acetal), melting point 171-173 ° (from methylene chloride / acetone).

Example 45

In analogy to Example 41, 6α-methyl-1,5-seco-A-trinorandrostane-5,17-dione-5- (ethynacetal) gives 6α-methyl-5-oxo-1,5-seco- A-trinor-17-α-pregnan-21,27-carbolactone, melting point 187-188 ° (from methylene chloride / hexane), [α] D + 3 ° (dioxane 0.5).

• 17ß-t-Butoxy-1,5-seco-A-trinorandrostan-5-on wird mit Lithiumdiisopropylamid-Methyljodid methyliert. Man erhält 17ß-t-Butoxy-6a-methyl-1,5-seco-A-trinorandrostan-5-on, Schmelzpunkt 140-141°.

The starting material was produced as follows:

• 17ß-t-Butoxy-1,5-seco-A-trinorandrostan-5-one is methylated with lithium diisopropylamide methyl iodide. 17β-t-Butoxy-6a-methyl-1,5-seco-A-trinorandrostan-5-one is obtained, melting point 140-141 °.

Cleavage of the t-butyl ether with acetic acid / perchloric acid and subsequent saponification gives 17β-hydroxy-6α-methyl-1,5-seco-A-trinor-androstan-5-one, melting point 124-125 °, from which 17ß-hydroxy by ketalization -6a-methyl-1,5-seco-A-trinorandrostan-5-one-ethylene acetal, melting point 192-193 ° is obtained.

Oxidation with Jones reagent finally gives 6a-methyl-1,5-seco-A-trinorandrostane-5,17-dione-5- (ethylene acetal).

Example 46

Analogously to Example 42, 6a-methyl-1,5-seco-A-trinorandrost-9 (11) -en-5,17-dione-5- (ethylene acetal) is used to obtain 6a-methyl-5-oxo-1 , 5-seco-A-trinorpregn-9 (11) -en-21,17-carbolactone, melting point 173-175 ° (from methylene chloride / ether), [α] D-41 ° (dioxane 0.5).

• Aus 17ß-t-Butoxy-6a-methyt-1,5-seco-A-trinorandrost 9(11)-en-5-on erhält man durch Spaltung des t-Butyläthers mit Essigsäure/Perchlorsäure und nachfolgende Verseifung mit methanolischer Kaliumhydroxydlösung das 17ß-Hydroxy-6a-methyl-1,5-seco-A-trinorandrost-9(11)-en-5-on, Schmelzpunkt 90-92° daraus durch Ketalisierung das 17ß-Hydroxy-6a-methyl-1,5-seco-A-trinorandrost-9(11)-en-5-on- äthylenacetal. Schmelzpunkt 180-182°.

The starting material is produced as follows:

• The 17ß is obtained from 17β-t-butoxy-6a-methyt-1,5-seco-A-trinorandrost 9 (11) -en-5-one by cleavage of the t-butyl ether with acetic acid / perchloric acid and subsequent saponification with methanolic potassium hydroxide solution -Hydroxy-6a-methyl-1,5-seco-A-trinorandrost-9 (11) -en-5-one, melting point 90-92 ° therefrom by ketalization, the 17β-hydroxy-6a-methyl-1,5-seco -A-trinorandrost-9 (11) -en-5-one-ethylene acetal. Melting point 180-182 °.

Jones oxidation gives 6α-Metbyl-1,5-seco-A-trinorandrost-9 (11) -en-5,17-dione-5- (ethylene acetal), melting point 128-129 °.

Example 47

Analogously to Example 1, 5-oxo-1,5-seco-D-homo-A-trinor-17at-pregnan-21,17a-carbolactone is used to obtain 5-oxo-1,5-seco-D-homo- A-trinor-17α-pregn-6-en-17a-carbolactone (isomer A). Melting point 227-228 ° (from acetone / hexane). UV λ = 229 nm, ε = 9,300. [Α] D - 113 ° (dioxane 0.2%) and as a by-product the 6-bromo-6-oxo-1,5-seco-D-homo-A-trinor -17ag-pregn-6-en-21,17a-carbolactone (isomer A).

From the corresponding isomer B, 5-oxo-1,5-seco-D-homo-A-trinor-17α-pregn-6-en-21,17a-carbolactone, (isomer B), melting point 167-168 ° (from acetone / hexane), UV λ = 229 nm, s = 9,900, [α] _D - 92 ° (dioxane 0.2) and as a by-product 6-bromo-5-oxo-1,5-seco-D -homo-A-trinor-17αζ-pregn-6-en-21,17a-carbolactone (isomer B), melting point 190-191 ° (from acetone / hexane), UV λ = 254 nm, ε = 7,800, [α ] D - 10 ° (dioxane 0.2) ..

• 1,5-Seco-A-trinorandrostan-5,17-dion-5-(äthylenacetal) wird mit Trimethylsulfoniummethoxysulfat und Kalium-t-butylat in Dimethylformamid zum Spiro [oxiran-2,17' (beta 1)-[1,5] seco-A-trinorandrostan]-5'-on-äthylenacetal, Schmelzpunkt 131-134° (Methanol) umgesetzt.

The starting material 5-oxo-1,5-seco-D-homo-A-trinor-17ag-pregnan-21,17a-carbolactone is produced as follows:

• 1,5-Seco-A-trinorandrostan-5,17-dione-5- (ethylene acetal) with trimethylsulfonium methoxysulfate and potassium t-butoxide in dimethylformamide becomes spiro [oxirane-2,17 '(beta 1) - [1,5 ] seco-A-trinorandrostan] -5'-one-ethyleneacetal, melting point 131-134 ° (methanol).

Reaction with ammonia gives the 17- (aminomethyl) -5,5- (äthytendioxy) -1,5-seco-A-trinorandrostan-17ß-ol, melting point 193-196 ° (crude product), from which the ring expansion by Tiffencan-Demjanow 1,5-Seco-A-trinor-D-homoandrostane-5,17a-dione-5- (ethylene acetal), melting point 137-138 ° (acetone / hexane) is obtained.

The two diastereomeric lactones 5-oxo-1,5-seco-D-homo-A-trinor-17aξ are obtained from this by lithium-Grignard with 3-bromo-propionaldehyde-dimethylacetal, cleavage of the two acetals with aqueous acetic acid and Jones oxidation -pregnan-21,17a-carbolactone.

Isomer A, melting point 200.5-201 ° (from acetone / hexane), [α] _D + 28 ° (dioxane 0.5%).

Isomer B, melting point 222-223 ° (from acetone / hexane), [α] _D + 24 ° (dioxane 0.5%).

Example 48

5 g of 5β-hydroxy-6,6-dimethyl-1,5-seco-A-trinorandrost-9 (11) -en-17-one are dissolved in 100 ml of tetrahydrofuran and 1.25 g of degreased pieces of lithium wire are removed under argon admitted. Then at about -25 ° within 2 hours, dropwise added 21.5 g of 3-bromopropionaldehyde dimethylacetal. When the addition is complete, the mixture is stirred for a further hour at this temperature, after which the cooling bath is removed and the mixture is stirred for a further hour, the temperature rising to about 20 °. The usual work-up provides 8.4 g of oil, which is used directly.

The entire crude product (8.4 g) thus obtained is dissolved in 30 ml of glacial acetic acid and 12.7 ml of water are added. After standing overnight, working up is carried out. 6.9 g of crude product are obtained.

The entire crude product obtained is dissolved in 40 ml of acetone and oxidized at room temperature with 10 ml of Jones reagent. The crude product (7.1 g) is chromatographed on 700 g Si0 ₂ with toluene-ethyl acetate. The appropriate fractions are pooled and crystallized from acetone-hexane. Pure 6,6-dimethyl-5-oxo-1,5-seco-A-trinor-17a-pregnen-9 (11) -en-21,17-carbolactone of melting point 139-141 ° is obtained in this way, [α] _D - 109 ° (dioxane 0.15).

• 17ß-t-Butoxy-6a-methyl-1,5-seco-A-trinorandrost-9(11)-en-5-on wird mit Lithiumdiisopropylamid/Methyljodid zum 17ß-t-Butoxy-6,6-dimethyl-1,5-seco-A-trinorandrost-9(11)-en-5-on, Schmelzpunkt 93,5-95,5° methyliert.

The starting material is produced as follows:

• 17ß-t-butoxy-6a-methyl-1,5-seco-A-trinorandrost-9 (11) -en-5-one is converted to 17ß-t-butoxy-6,6-dimethyl-1 with lithium diisopropylamide / methyl iodide, 5-seco-A-trinorandrost-9 (11) -en-5-one, melting point 93.5-95.5 ° methylated.

Lithium aluminum hydride reduction gives 17β-t-butoxy-6,6-dimethyl-1,5-seco-A-trinorandrost-9 (11) -en-5ß-ol, melting point 163-164 °.

Acetylation with pyridine / acetic anhydride at elevated temperature gives 17β-t-butoxy-6,6-dimethyl-1,5-seco-A-trinorandrost-9 (11) -en-5ß-ol acetate, melting point 129-130 °.

Cleavage of the t-butyl ether with acetic acid / perchloric acid and subsequent saponification with potassium carbonate in methanol gives 5β-acetoxy-6,6-dimethyl-1,5-seco-A-trinorandrost-9 (11) -en-17ß-ol. Melting point 134-135 °.

Jones oxidation gives the 17-ketone 5β-acetoxy-6,6-dimethyl-1,5-seco-A-trinorandrost-9 (11) -en-17-one, melting point 135.5-136 ° or by boiling saponified in methanolic potassium hydroxide solution to give 5β-hydroxy-6,6-dimethyl-1,5-seco-A-trinorandrost-9 (11) -en-17-one. Melting point 175-175.5 °.

Example 49

In analogy to Example 36, the potassium 17-hydroxy- is obtained from 6,6-dimethyl-5-oxo-1,5-seco-A-trinor-17a-pregn-9 (11) -en-21,17-carbolactone. 6,6-dimethyl-5-oxo-1,5-seco-A-trin _Q r-17a-pregna-9 (11) -en-21-carboxylate. Melting point 261-263 °, [α] _D - 67 ° (EtOH, c = 0.5%).

Example 50

In analogy to Example 48, 5β-hydroxy-6,6-dimethyl-1,5-seco-A-trinorandrostan-_17-one becomes 6,6-dimethyl-5-oxo-1,5-seco-A-trinor -17a-pregnan-21,17-carbolactone obtained. Melting point 126-129 ° (from acetone / hexane), [a] _D - 58 ° (dioxane c = 0.2).

• 17ß-t-Butoxy-6a-methyl-1,5-seco-A-trinorandrostan-5-on mit Lithiumdiisopropylamid/Methyljodid zum 17ß-t-butoxy-6,6-dimethyl-1,5-seco-A-trinor-androstan-5-on, Schmelzpunkt 123-124° methyliert.

The starting material is produced as follows:

• 17ß-t-butoxy-6a-methyl-1,5-seco-A-trinorandrostan-5-one with lithium diisopropylamide / methyl iodide to give 17ß-t-butoxy-6,6-dimethyl-1,5-seco-A-trinor- androstan-5-one, melting point 123-124 ° methylated.

Reduction of the 5-ketone with sodium borohydride and subsequent acetylation yields 5β-acetoxy-17ß-t-butoxy-6,6-dimethyl-1,5-seco-A-trinorandrostane, melting point 117-118 °.

Cleavage of the t-butyl ether and subsequent treatment with potassium carbonate in methanol leads to 5β-acetoxy-6,6-dimethyl-1,5-seco-A-trinorandrostan-17ß-ol, melting point 149-151 °.

Jones oxidation gives 5β-acetoxy-6,6-dimethyl-1,5-seco-A-trinorandrostan-17-one, melting point 132-133 ° from which the 5ß-hydroxy-6,6-dimethyl-1 is obtained by saponification, 5-seco-A-trinorandrostan-17-one, melting point 183-184 ° is obtained.

Example 51

In analogy to Example 48, the potassium 17-hydroxy-6,6-dimethyl-5 is obtained from 6,6-dimethyl-5-oxo-1,5-seco-A-trinor-17a-pregnan-21,17-carbolactone -oxo-1,5-seco-A-trinor-17a-pregnan-21-carboxylate, melting point 274-284 ° (isopropanol), [α] _D - 38 ° (methanol 0.5%).

Example A

A tablet for oral administration can have the following composition:

Example B

A capsule for oral administration can have the following composition:

Claims (12)

1. DeA-steroids of the formula

wherein R¹ and R² signify hydrogen or C_1-5-alkyl ; R³ signifies hydrogen, methyl or halogen ; R⁴ signifies hydrogen or, where R³ is methyl, R⁴ signifies hydrogen or methyl ; R⁵ signifies hydrogen, cyano, C_1-5- alkoxy or a residue SR⁷ ; or R³ and R⁵ together signify methylene ; R⁶ signifies hydrogen C_1-7- alkanoylthio ; R⁷ signifies C_1-7-alkanoyl, C_1-8-alkyl, benzyl or phenethyl ; X signifies oxo or methylene ; Y signifies hydrogen ; Z signifies hydroxymethyl or a group ―COA; A signifies hydroxy.; or Y and A together signify a O-C bond ; n is 0 or 1 and the dotted bonds in the ring are optional ; whereby each ring contains at most one double bond ; the ring B is 9(10)-unsaturated when the ring C is 11(12)-unsaturated ; at least one residue R⁵ or R⁶ is hydrogen ; R⁵ is hydrogen when R⁴ is methyl ; R⁵ is hydrogen or R³ and R⁵ together are methylene and R⁶ is hydrogen when Z is carboxy ; R³ is hydrogen, methyl or halogen and R⁴ is absent when a 6(7)- or 7(8)-double bond is present ; the 6(7)- and 11 (12)-bond is saturated when R⁶ is C_1-7-alkanoylthio ; and R¹ is absent and R² is C_1-5-alkyl when a 9(10)-double bond is present, the rings C and D are saturated, n is 0 and Z is a group -COA, or salts of compounds of formula in which Z is a carboxyl group, for use as pharmaceuticals.

2. DeA-steroids in accordance with claim 1 of the formula

wherein R¹, R², R³, R⁵, A, Y, n and the dotted bonds have the significance given in claim 1, for use as pharmaceuticals.

3. DeA-steroids of formula I or 1-1 in accordance with claim 1 or 2, in which at least one residue R¹ or R² is C_1-5-alkyl, for use as pharmaceuticals.

4. DeA-steroids of formula I or 1-1 in accordance with claim 1 or 2, in which the rings B and C are unsaturated, for use as pharmaceuticals.

5. DeA-steroids of formula I in accordance with claim 1, in which Z is hydroxymethyl, for use as pharmaceuticals.

6. 5-Oxo-A-tetranor-17α-pregna-9,11-diene-21,17-carbolactone, for use as a pharmaceutical.

7. DeA-steroids of the formula

wherein R¹ and R² signify hydrogen or C_1-5-alkyl ; R³ signifies hydrogen, methyl or halogen ; R⁴ signifies hydrogen or, where R³ is methyl, R⁴ signifies hydrogen or methyl ; R⁵ signifies hydrogen, cyano, C_1-5- alkoxy or a residue SR⁷ ; or R³ and R⁵ together signify methylene ; R⁶ signifies hydrogen or C_1-7- alkanoylthio ; R⁷ signifies C_1-7-alkanoyl, C_1-8-alkyl, benzyl or phenethyl ; X signifies oxo or methylene ; Y signifies hydrogen ; Z signifies hydroxymethyl or a group ―COA; A signifies hydroxy ; or Y and A together signify a O-C bond ; n is 0 or 1 and the dotted bonds in the ring are optional ; whereby each ring contains at most one double bond ; the, ring B is 9(10)-unsaturated when the ring C is 11(12)-unsaturated ; at least one residue R⁵ or R⁶ is hydrogen ; R⁵ is hydrogen when R⁴ is methyl ; R⁵ is hydrogen or R³ and R⁵ together are methylene and R⁶ is hydrogen when Z is carboxy ; R³ is hydrogen, methyl or halogen and R⁴ is absent when a 6(7)- or 7(8)-double bond is present ; the 6(7)- and 11 (12)-bond is saturated when R⁶ is C_1-7-alkanoylthio ; and the rings B and C are unsaturated, and salts of compounds of formula I in which Z is a carboxyl group.

8. DeA-steroids in accordance with claim 8 of the formula

wherein R¹, R², R³, R⁵, A, X, A, Y, n and the dotted bonds have the significance given in claim 8.

9. DeA-steroids in accordance with claim 8 or 9, in which at least one residue R¹ or R² is C_1-5-alkyl.

10. DeA-steroids in accordance with any one of claims 8, 9 or 10, in which Z is hydroxymethyl.

11. 5-Oxo-A-tetranor-17α-preg na-9,11-diene-21,17-carbolactone.

12. A process for the manufacture of the deA-steroids defined in claim 7, characterized by

a) oxidizing the group OR⁸ in a compound of the formula

to the oxo group ; or

b) dehydrogenating a compound of the formula

or the corresponding acid or a salt thereof in the 6(7)- or 7(8)-position ; or

c) halogenating a compound of the formula

or the corresponding acid or a salt thereof ; or

d) reacting a compound of the formula

with a compound R⁷SH, a C_1-5-alkanol or hydrogen cyanide ; or

e) reacting a compound of the formula

the corresponding acid or salt thereof with a methylenephosphonium compound according to Wittig ; or

f) opening the lactone ring in a compound of the formula

or

g) in a compound of formula I in which Z represents the group COA, reducing this group to the hydroxymethyl group ; whereby in the above formulae R¹, R², R³, R⁴, X, n and the dotted bonds in the ring have the significance given above and R⁸ represents hydrogen or C_1-8-alkyl.